Visual deprivation and blindness famously cause certain brain regions to reorganize in response to environmental constraints and in order to compensate for the loss of a sensory modality. Studies in visually deprived animals and blind humans have long demonstrated the cross-modal recruitment of the visual cortex to process nonvisual information. Yet, little is known about the functional specialization of the reorganized visual cortex (VC), its precise role in the processing of nonvisual information, or the source and routing of its nonvisual inputs. The main aims of the present project are, therefore, to (1) determine the functional organization of the occipital cortex in blind volunteers using a sensory substitution device, (2) to examine whether nonvisual information is processed hierarchically in the VC of the blind, and (3) identify the structural basis of adaptive changes and the source of nonvisual input to VC in the blind. Results from three years of funding by this grant have demonstrated that spatial and nonspatial processing streams do indeed exist for auditory and tactile processing (Renier et al., 2009). Furthermore, spatial auditory and tactile processing in the VC of the early blind occur in the same dorsal-stream regions as visual spatial processing in sighted subjects (Renier et al., 2010). These findings have led us to hypothesize that functionally specialized modules are preserved in the cortex of the early blind. We will pursue this hypothesis further by testing paradigms within the ventral stream. Thus, using functional magnetic resonance imaging, we will examine brain activity in blind subjects while they identify (via the auditory modality) houses, faces and 2-D geometrical shapes coded into sound patterns. These experiments will allow us to determine whether the parahippocampal place area (PPA), the fusiform face area (FFA), and the lateral occipital complex (LOC) retain their designated functional roles in early blindness, while switching their input modality. We will also examine the organization of VC by testing whether nonvisual information is processed in a hierarchical manner, in the same way that normal sensory information is processed in its intact sensory system. Using complexity-varied pitch information, we will determine if early-to-late visual regions of the blind respond to sound in the direction of simple-to-complex levels of pitch processing. Finally, using diffusion tensor imaging (DTI) and analysis of functional connectivity, we will investigate the structural basis of adaptive changes in the cerebral cortex and white matter of blind subjects. Using DTI, we will examine the strength of white-matter fiber tracts projecting to and from VC in both subject groups, thus determining relative changes in the connections between VC and other cortical areas. We will also test how visual and other sensory areas interact during auditory and tactile information processing in blind and sighted volunteers, and whether this interaction depends on the strength of anatomical pathways connecting these areas. Combining the two different methodological approaches will provide us an excellent opportunity to identify the source of nonvisual inputs to VC in the early blind.